1. Field of the Invention
This invention pertains to retinoid derivatives showing phospholipase A.sub.2 (PLA.sub.2) inhibitory activity, and pharmaceutical preparations comprising these compounds. Similarly, a method of inhibiting PLA.sub.2, in mammals, is addressed.
2. Background of the Prior Art
Phospholipases are enzymes which catalyze the hydrolysis of membrane phospholipids releasing free fatty acids. In mammalian tissues, phospholipase A.sub.2 (PLA.sub.2) is a calcium-dependent enzyme which specifically cleaves the sn-2-acyl bond of phospholipids to yield free arachidonic acid and a lysophospholipid. [Van den Bosch H. Biochem Biophys Acta, 604,191-246 (1980)]. Both products of this reaction can serve as starting points for the biosynthesis of inflammatory mediators. Arachidonic acid can be converted by the cyclooxygenase and lipoxygenase pathways to the proinflammatory prostaglandins and leukotrienes. [Higgs GA and Vane JR, Br Med Bull, 39, 265 (1983)]. Lysophospholipids can be utilized by certain cell types to produce platelet-activating-factor (PAF), a potent inflammatory mediator. [Chilton FH et al, J. Biol Chem, 257, 5402 (1982)].
Many non-steroidal anti-inflammatory agents, such as indomethacin, inhibit the cyclooxygenase reaction and therefore block the formation of prostaglandins from arachidonic acid. A number of compounds also have been discovered which are lipoxygenase inhibitors. [Gordon Jones et al, J. Med Chem, 29, 1504-1511 (1986)]. [Mardin M and Busse WD, In: Leukotrienes and other Lipoxygenase Products, (Ed) P. J. Piper, Prostaglandin Series, pp. 3, 263-274, Chichester Research Studies Press]. These compounds block the formation of leukotrienes and have also been shown to have anti-inflammatory effects. In addition, several compounds have been reported to be dual lipoxygenase/cyclooxygenase inhibitors [Salmon J A, Simmons P M and Moncada S H, J Phar Pharmac 35, 808 (1983)]. [Bonney R J et al, Biochem Pharmacol, 36, 22, 2885-2891 (1987)]. It is thought that these compounds, by virtue of their more complete blockade of the arachidonic acid cascade, would be more effective anti-inflammatory agents. An inhibitor of phospholipase A.sub.2 would be expected to reduce the production of the same mediators as would a dual lipoxygenase/cyclooxygenase inhibitor. However, this reduction would be achieved via inhibition of arachidonic acid release. In addition, inhibition PLA.sub.2 would result in a reduction of PAF production. As a result, inhibition of PLA.sub.2 activity represents an attractive approach for the development of novel agents for the treatment of inflammatory disorders.
A wide variety of retinoids, and related retinoic acid derivatives, are known in the art. Thus, U.S. Pat. No. 4,568,757, Carroll et al, discloses configurationally locked retinoids. U.S. Pat. Nos. 4,126,693 and 4,055,659, Gander et al, as well as U.S. Pat. No. 4,194,007 describe various retinoids which are generally esters and amides of trans-retinoic acid as well as derivatives thereof. These patents generally ascribe "vitamin A-type activity" to the various retinoids described therein, and specifically describe the use of these compounds in the treatment of skin diseases or abnormal states, abnormal keratinization, acne, etc., as well as their use as sunscreen agents.
Additional art references are available describing the preparations of various retinoids and retinoid intermediates. U.S. Pat. No. 2,662,914, describes a retinoic acid derivative with a carboxylic acid substituent at the 14 position, while Lewin et al, [Journal of Organic Chemistry, 48, 222 (1983) and Journal of American Chemical Society, 103, 2527 (1981)] describe the synthesis of various retinoids. Other retinoids, and PLA.sub.2 inhibitors are addressed in C. Fiedler [Nagy et al, Agents and Actions, 46, 620-621 (1985) and 27, 313-315 (1989)]; A. A. Fawzy et al, [Agents and Actions, 25, 394-400 (1988)]; A. C. Hanglow et al, [Agents and Actions, 27, 347-350 (1989)] and C. Marcelo et al, [Clin. Res., 34, 766A (1986)].
It is the object of this invention, therefore, to provide retinoid compounds which have PLA.sub.2 inhibitor properties, and compositions including those compounds which are useful in the treatment of inflammatory diseases, such as arthritis, inflammatory bowel disorder and numerous related conditions characterized by manifest inflammation.